The topographic distribution, morphology and pattern of fiber staining of nicotinamide adenine dinucleotide-diaphorase (NADPH-d) containing structures was shown to be largely similar in the amygdala of the squirrel monkey and normal aged human. NADPH-d cells are resistant to neurodegeneration in Huntington's disease and may be resistant to neurodegeneration in Alzheimer's disease (AD). The selective vulnerability hypothesis was tested in the hippocampal formation and amygdala in patients with AD, demonstrating up to a 50% decrease in neurons containing the calcium-buffering protein, parvalbumin. Those areas connectionally associated with the cerebral cortex, e.g., the dentate gyrus, CA1 and lateral nucleus of the amygdala, showed the significant declines in the number and morphologic diversity of parvalbumin neurons. This suggests that connectivity of a specific cytoarchitectural area features in the pathogenesis of AD. A molecular biology approach toward understanding the role of long projection neurons was undertaken using cDNA clones derived by differential hybridization. This revealed cytochrome oxidase (COX) mRNA was differentially expressed in long projection neurons as compared to small interneurons. Moreover, COX enzyme activity was differentially expressed in terminal fields of long projection systems, e.g., the perforant pathway in the hippocampal formation. A major goal of many research labs is the generation of a useful animal model for AD. We evaluated a transgenic mouse model whose transgene contained the carboxy-terminal 100 amino acids of the amyloid precursor protein. There was no evidence of increased beta-amyloid protein expression in murine brain, nor any neuropathologic changes even remotely similar to AD.